HU190648B - Process for preparing n-substituted 2,3,4,5-tetra-hydro-1h-3-benzazepine derivatives - Google Patents

Abstract

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Description

The present invention relates to N-substituted 2,3,4,5-tetrahydro-1H-3-benzazepines and their acid addition salts, and to pharmaceutical compositions containing the above derivatives as active ingredients.

The compounds of the present invention exhibit a broad antagonism of cardiovascular (cardiovascular) activity by reducing intraocular pressure (intraocular pressure).

The pharmaceutical compositions of the present invention are useful, inter alia, for the treatment of congestive or hypotensive heart failure, angina pectoris and thrombosis.

The compounds of the present invention also have antihypertensive activity and, because of their advantageous effect, may also be used as an active ingredient in antihypertensive agents.

The reduction of intraocular pressure plays an important role in the treatment of glaucoma (glaucoma), as the above-mentioned eye disease is characterized by increased intraocular pressure. Glaucoma is the most common disease causing blindness in people over the age of forty. In fact, as the glaucoma progresses inadequately, intraocular pressure increases continuously, resulting in severe degeneration of the retina and optic nerves. If glaucoma is not treated, the eyes will be red and painful, eyesight will deteriorate, and eventually the patient will become blind.

The three most commonly used anti-glaucoma agents are pilocarpine, timolol and epinephrine. Pilocarpine causes pleural effusion and radiation cramps, resulting in blurred vision and nearsightedness. Epinephrine dilates the pupil and causes blurred vision, and causes congestion, blemish edema and allergic reactions to the eyes. In addition, epinephrine is absorbed into the body and causes irregular heartbeat. Timolol has fewer side effects on the eye, but many side effects are known throughout the body. Bradycardia (low heart rate), fainting, an increase in indeterminate heart failure, and bronchospasm have already been observed following topical treatment with timolol.

A further disadvantage of epinephrine is that it is unstable to air and light and that it chemically reacts with many of the additives commonly used in pharmaceutical formulations. Efforts to overcome the above disadvantages have generally resulted in compositions that are irritating or biologically inactive to body tissues.

The pharmaceutical compositions of the present invention, when applied topically as eye drops, are useful for the treatment of glaucoma by reducing intraocular pressure. They have the advantage that they do not directly affect pupil size, do not alter the blood pressure of subjects with normal blood pressure, and have minimal local or systemic adverse effects.

Thus, the pharmaceutical compositions of the present invention unexpectedly reduce intraocular pressure without having the adverse, undesirable side effects of the agents described above.

U.S. Patent Nos. 4,210,749 and 4,233,217 disclose a number of benzazepine derivatives having analgesic, antihistamine and narcotic antagonistic properties. However, neither of the benzazepine derivatives of formula (I) nor their β-antagonist activity have been specifically mentioned in the above literature. One of the benzazepine derivatives of formula (I), 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, is known as an intermediate from U.S. Patent No. 4,265,890. , however, no useful biological activity of the compound was mentioned in the above patent. U.S. Patent Nos. 3,716,639 and 3,752,892 disclose the appetite suppressant effect of 7-chloro and 6-chloro-2,3,4,5-tetrahydro-1d-3-benzazepines.

None of the above patents mention the above-mentioned biological activity and applicability of the benzazepine derivatives of general formula (1) as a pharmaceutical composition.

The active compounds of the present invention are benzazepines of formula (I) or pharmaceutically acceptable acid addition salts thereof. In the general formula (1)

R is lower C 1-3 lower alkyl or allyl, and

X is halogen, preferably chlorine, bromine or fluorine.

Among the pharmaceutical compositions of the present invention, benzazepine of formula (I) which is substituted with R is methyl and X is chloro is preferred, i.e. 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3- Preparation containing benzazepinl.

The antagonist active compounds of formula (I) may be prepared by conventional procedures. The most advantageous solution is

This is illustrated in Scheme 1. The substituents X and R in the formula are as defined above.

According to the process of the invention, the (halophenyl) acetic acid is treated with thionyl chloride followed by the appropriate amino alcohol. The resulting amide is reduced with a known reducing agent, such as borane. The resulting amino alcohol is converted to the corresponding halide such as chloride or bromide and then cyclized by Friedel-Crafts reaction. The ring closure is carried out in the presence of a Lewis acid such as aluminum chloride, aluminum broinide, titanium chloride or antimony chloride. The ring closure is preferably carried out in a melt of aluminum chloride and ammonium chloride at high temperature.

Alternatively, the compounds of formula (I) may be prepared by treating the corresponding benzazepine containing R with hydrogen by treatment with an alkylating or acylating agent to replace the hydrogen atom with the desired R. The alkylating or acylating agent used is a compound of formula RY or RCOY wherein R is as defined for formula (I) and Y is halogen, preferably chlorine or bromine. Aldehydes or ketones may also be used as reagents. In this case, the reaction is followed by reduction. The reduction can be effected catalytically, for example with hydrogen in the presence of a platinum catalyst, or chemically with, for example, sodium borohydride or sodium cyanoborohydride.

When the substitution is carried out with a reagent of the formula RCOY, the carbonyl group is reduced in the next step, for example with lithium aluminum hydride.

Pharmaceutically acceptable acid addition salts, which are equivalent to the free bases of formula (I), are prepared from inorganic or organic acids in the known manner from the appropriate bases. Organic or inorganic acids include, for example, raalic acid, fumaric acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid, bis-methylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, oxalic acid, propionic acid, palic acid, citric acid, glutamic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, hydrogen chloride, hydrobromic acid, sulfuric acid, cyclohexylsulfamic acid, phosphoric acid or nitric acid can be used.

The in vitro biological activity of the compounds of formula (I) according to the present invention is demonstrated by the presence of a pre-bound receptor antagonist activity in the isolated, perfused guinea pig in the left atrium. The assay is performed by excisioning the heart of a male guinea pig anesthetized with pentobarbital. The left atrium was removed, freed of foreign tissue, and attached to a 2 ml perfusion chamber. The tissue is prepared at a rate of 60 pulses per minute and the sympathetic nerves are excited by surface stimulation every 6 minutes. The response to the nerve stimuli is measured as the difference between the contraction forces required to induce basic contraction and the maximum contraction after stimulation. The concentration-response curve of clonidine (? -Anogist) is determined by increasing the concentration of clonidine in the preparation after each stimulation. The tissue is then perfused with the test antagonist compound for 30 minutes, and the clonidine concentration-response curve is again plotted in the presence of the antagonist. By antagonist compound dissociation constant (Ki) is meant the antagonist concentration required to shift the curve of the agonist compound by 2 units to the right.

The selectivity of the compounds for the? -Receptor relative to its ability to bind to the? 1-adrenoceptor is determined by comparing the Kb value obtained above with the Kb value obtained with the tci receptor. The latter is measured in a rabbit carotid artery block by antagonizing norepinephrine-induced contraction. Hieble and Pendleton [Arch. Pharmacol. 309, 217 (1979)].

The preferred compound of the present invention, 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine, has a Kb value of 13 nM in isolated, perfused guinea pig left atria.

When the halogen substituent is located at the 7-position of the benzazing ring, the activity is greatly reduced. For example, the Kb of 7-chloro-2,3,4,5-tetrahydro-3-melyl-1H-benzazepine is 150 nM, i.e. about one tenth of the? -Agonist activity of the 6-chloro derivative. When the compound contains an amino group at the 6-position or a similar substituent, or the 6-and 7-carbon atoms are incorporated into a cyclopentane ring, the resulting compounds are completely inactive with respect to their? -Agonist activity.

The in vivo antihypertensive activity of the compounds of the present invention is tested as follows.

Male rats (300-450 g) were anesthetized with sodium brevital and cannulated into the femoral vein and artery. The cannula stroke is guided under the skin until it is visibly positioned on one side around the posterior sacrum and secured there with a wound clamp. The animals are placed in a small cage and wait until they wake up. The cannula inserted into the artery is attached to a pressure transducer to maintain constant blood pressure and control heart function. The test compounds are administered either orally by gavage or intravenously through the femoral vein cannula at a rate of 0.06 ml / min.

The above test is performed on both normal blood pressure and hypertensive (hypertensive) animals. DOCA salt hypertensive animals were obtained from Spargue-Dawley male rats with one kidney removed. Rats, approximately 6 weeks of age, were lightly anesthetized with ether and subcutaneously injected with 25 mg of deoxycorticosterone acetate tablets.

Table 1 in. Fish a day later, we also implanted a tablet around the sacral bone. Rats are fed with standard laboratory food but water (1%) instead of water. The rats were watered with saline for 22-24 days.

Table 1 shows the blood pressure lowering effect of 6-chloro-2,3,4,5-tetrahydro-3-ylethyl-β-3-benzazepine i.v. when administered to normal blood pressure Ó3 hypertension rats.

Palkányfajta

Diastolic blood pressure

Injection of compound Reduction in blood pressure (minHg) (mmHg) 0.5 mg / kg 1.0 mg / kg

arc. dose

Normal blood pressure (control)

Spargue-Dawley, n = 4 95+ 7 6 ± 2 13 ± 1 DOCA salt is hypertensive 135 ± 5 27 ± 3 33 ± 4 n - 4 Normal blood pressure 115+ 3 7 ± 2 10 i 2 (Control) Wistar-Kyoto, n = 4 Spontaneously hypertensive 167+ 3 33 ± 7 46 ± 2

n = 7 n - number of animals

The data in Table 1 show that while the effect of 6-chloro-2,3,4,5-telrahydro-3-methyl-1H-3-benzazepine on the blood pressure of animals with normal blood pressure is low, it is hypertensive when treated with DOCA salt. and spontaneous hypertensive animals significantly reduced diastolic blood pressure. Comparing the data obtained at doses of 0.5 mg / kg and 1.0 mg / kg, the antihypertensive effect is dose-dependent.

The antihypertensive effect of 6-chloro-2,3,4,5-tetrahydro-3-nielyl-1H-beuzazepine was also determined in rats dosed with DOCA salt by oral administration. The results are reported in Table 2.

Table 2

Dose po (Mg / kg) Medium arterial pressure (mmHg) Hypotension (MmHg) treatment before treatment after 2 148 ± 11 131 ± 12 17 ± 3 5 160 ± 7 127 ± 5 34 + 4 10 167 ± 8 99 ± 4 68 ± 8

The pharmaceutical compositions of the present invention are also used to treat cardiovascular disorders with liazide-type diurelics, such as hydrochlorothiazide, triacinone, calcium blocking agents such as Verapamil or Nifedipine, or with adrenergic blocking agents such as propranol.

The above combination pharmaceutical compositions may contain, in addition to 25 to 500 mg of the active ingredient of the formula I, 2 to 250 mg of thiazide, 5 to 250 mg of triamterene or 1 to 500 mg of calcium channel blocking compound.

Another effect of the compounds of formula I according to the invention is their ability to reduce intraocular pressure. The principle of intraocular pressure is to exert a force on the eye that causes it to squeeze or drain. Either the effect of a force of a given magnitude or the force required to achieve that effect is measured. The intraocular pressure-lowering effect of the compounds of formula (I) of the present invention on rabbits is determined by West, C., Capella, J. and Kaufmari, H. Am. J. Opthalniol. 74, 505 (1972)], the following rao60 don. Proparacaine hydrochloride 0.5% solution was diluted ten-fold with physiological saline and instilled into the rabbit eye. Gently massaging the eyelids over the azulea will distribute the solution evenly. The eyes will be exposed by separating the eyelids-49

J 90648 is narrow and the tip of the probe is slowly placed on the cornea, at the point where the corneal curvature is greatest, i.e., on the optical axis. With the help of the Alcon Applanation Pneumatograph, intraocular pressure is determined in both eyes while a constant value is obtained.

Each study was performed on nine rabbits with three animals per dose. The initial intraocular pressure, t = 0, was determined in each case in both eyes. After reading the initial pressure value, the test compounds were instilled into the eye in the form of a 0.01% to 10% drug solution, and the pressure values were read at 0.5, 1, 2, 3, 4 and 6 hours after instillation. The intraocular pressure is calculated from the values recorded on the pneumatic chart paper. At each time point, the mean intraocular pressure is calculated. The preferred compound of the invention, 6-chloro-2,3,4,5-tetrahydro-3-diethyl-1H-3-benzazepine, is distinguished by an hourly depressant effect after instillation, which is critical for the desired biological effect. .

Unexpectedly, it has also been discovered that the preferred compound, 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine, is administered internally, i.e., not locally, and by measuring intraocular pressure, the compound reduces intraocular pressure without significantly affecting the body's blood pressure. For example, when the compound is infused into the ear vein of alert, normal blood pressure rabbit at a dose of 0.5 mg / kg, the compound reduces intraocular pressure by 4-5 min / g after one hour.

Pharmaceutical compositions intended to produce a? -Agonist effect and to lower blood pressure contain a benzazepine derivative of the Formula I as an active ingredient in admixture with a pharmaceutically acceptable carrier. The active ingredient is contained in an amount sufficient to produce the antagonism and the antihypertensive effect.

Compositions for the above purposes preferably contain from 25 to 500 mg, preferably from 50 to 250 mg, of active ingredient per dosage unit.

Pharmaceutically acceptable carriers may be solid or liquid carriers. The solid carriers include lactose, magnesium stearate, magnesite, sucrose, talc, stearic acid, gelatin, agar, pectir or acacia. The amount of solid carrier can vary widely, preferably between 25 mg and 1 g. Liquid carriers include, for example, syrup, peanut oil, olive oil, sesame oil, propylene glycol, polyethylene glycol (molecular weight 200-400) or water. The carrier or diluent may also contain a known delayed release excipient, such as glyceryl monostearate or glyceryl distearate, neat or in combination with wax.

The pharmaceutical compositions may be formulated in various forms, including tablets, capsules, powders, troches, lozenges, syrups, emulsions, sterile injectable solutions or liquid suspensions or solutions.

The pharmaceutical compositions are prepared in a conventional manner, for example by mixing, granulating, crushing or dissolving the ingredients, according to the desired composition.

The compounds of formula (I) are preferably administered in the form of conventional dosage units which are prepared by admixing the appropriate amount of the active ingredient with excipients conventionally used in the preparation of pharmaceuticals.

The daily dose of the active compounds of the formula I is preferably 100-1000 mg, more preferably 200-500 mg. The daily dose is preferably administered in 2-4 equal doses.

The pharmaceutical compositions for reducing intraocular pressure consist of a pharmaceutical carrier, preferably a carrier commonly used in formulations for the treatment of intestines, and the benzazepine derivatives of the formula (I) as an active ingredient. The active ingredient is contained in an amount sufficient to provide a reduction in intraocular pressure. The above compositions preferably contain from 0.01% to 5% of the active compound of formula (I), more preferably from 0.03% to 3.0%.

Formulations suitable for the treatment of the eyes may be in solid or liquid form. Liquid carriers include, but are not limited to, the standard 1.9% isotonic boric acid solution, 0.9% sodium chloride solution, or sodium borate solution. In addition, traditional phosphate buffer solutions, such as the Sorensen phosphate buffer side pH 6.8, can be used as a liquid carrier. Among the solid carriers there may be mentioned conventional balsamic bases such as petroleum jelly.

The above pharmaceutical compositions of the present invention will generally be administered topically to the eye in unit dosage form, for example, as solutions, balms, creams, gels or dispersions suitable for eye treatment. Controlled release of the compound is desired

In the case of -5II, polymeric ophthalmic systems known to those skilled in the art from, for example, U.S. Patent 4,052,505 are available.

The ophthalmic solutions are sterile and may contain, in addition to the active compound of formula (I), antimicrobial agents, such as quaternary ammonium salt germicides such as bis-alkonium chloride, benzethonium chloride or cetylpyridinium chloride. In addition, chlorobutanol or phenylmercury nitrate may be used for the above purposes. If desired, sodium sulfite, sodium ascorbate or other commonly used antioxidants, such as oxime sulfate, may be added as the antioxidant.

The benzazepine active ingredient of the formula I is preferably administered in the form of an ophthalmic dosage unit form which is prepared by admixing the appropriate amount of the active ingredient with the above acceptable carriers. The dosage form suitable for treating the eye is preferably administered 2 to 4 times daily. For example, eye drops are given 1 to 5 drops 2-4 times a day.

When used as described above, the active compounds of the formula I can achieve antagonism, antihypertensive activity and intraocular pressure lowering activity.

The following examples illustrate the invention.

Example 1

A mixture of 125 g (0.73 mol) of o-chlorophenylacetic acid, 155 g (1.3 mol) of thionyl chloride, 2-3 drops of dimethylformamide and 1500 ml of toluene was stirred at room temperature for 3 hours. The toluene was evaporated under reduced pressure to give an oily residue which was dissolved in methylene chloride (200 mL). The above solution was added dropwise to a solution of N-methylaminoethanol (165 g, 2.2 mol) in methylene chloride (1000 mL). After the addition was complete, the solution was stirred at room temperature for 3 hours. The organic solution was washed with water, dilute hydrochloric acid and brine, dried over magnesium sulfate, filtered and evaporated. 77% C. 2-chloro-N- (2-hydroxyethyl) -N-methylphenylacetamide is obtained as a crystalline solid.

To a 1 M solution of borane in 400 ml of telrahydrofuran at reflux temperature, a solution of 43 g of the above amide in 350 ml of tetrahydrofuran was added dropwise so as to keep the solution slightly boiling. After the completion of the dropwise addition, the solution was refluxed for a further 2 hours, cooled in an ice bath and the excess borane was decomposed by the careful addition of dilute hydrochloric acid.

Most of the solvent was removed in vacuo and the residue was heated on a steam bath for 1 hour. The material was diluted with water (300 mL) and extracted with ether. The aqueous phase was made basic with 40% sodium hydroxide and extracted with ether. The combined alkaline extracts were washed with water and saturated sodium chloride and dried. After evaporation, 2 - {[2- (2-chlorophenyl) ethyl] methylamino) ethanol is obtained.

To a solution of phosphorus pentachloride (g, 0.173 mol) in methylene chloride (300 ml) was added dropwise 2- (2- (2- (2-chlorophenyl) ethyl) methylamino} ethanol (37 g) in methylene chloride (50 ml). At the end of the dropwise addition, the mixture was refluxed overnight, evaporated to dryness and partitioned between dilute hydrochloric acid and ether, basified with 10% sodium hydroxide and extracted with ether, and the ether extracts were washed with water and After washing with sodium chloride, drying over magnesium sulfal and filtration, the filtrate is added with ethereal saturated ether, the precipitate is filtered off, washed with ether and dried 2 / chloro-N- (2-chloroethyl) -N-ethylphenyl ethyl hydrogen chloride, m.p. 110 ° C.

To a mixture of 41.5 g (0.155 mol) of the above chloroallylamine hydrochloride and 6.26 g (0.117 mol) of ammonium chloride is added 41 g of anhydrous aluminum chloride. The molten homogeneous reaction mixture exothermic was placed in an oil bath at 175 ° C and stirred for half an hour. Another 20 g of aluminum urea chloride was added to the melt and heated for an additional 30 minutes. Finally, 41 g of aluminum chloride are added to the reaction mixture and the mixture is heated for 20 hours. The mixture was then cooled to 140 ° C, poured into 3 L of ice water containing 300 mL of concentrated hydrochloric acid and stirred for 15 minutes. Add 60 g of potassium potassium tartrate and mix until completely dissolved. It is made basic with 40% sodium hydroxide solution, extracted twice with ether, the combined extracts are washed with water and then with saturated sodium chloride, dried and concentrated to half volume under reduced pressure. Saturated ethereal hydrogen chloride solution was added to the side, the precipitate was filtered off, washed with ether and dried. The resulting white solid was recrystallized from methanol / ethyl acelate. 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is obtained, m.p. 268-270 ° C.

Example 2

To a solution of 1.2 g of 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 30 ml of toluene is added, while stirring at 50 ° C, 0.7 g of cyanobromide dropwise, dissolved in toluene. After completion of the dropwise addition, the solution was heated at 50 ° C for one hour with stirring. During the reaction

-613

190643 nitrogen gas was passed over the surface of the solution. The mixture was cooled, filtered and the filtrate concentrated in vacuo. The resulting 6-chloro-3-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 81-82 ° C after recrystallization from hexane / ether.

The mixture of 6-chloro-3-cyano-2,3,4,5-tetrahydro-1H-3-benzazepinyl in glacial acetic acid and 30 ml of 6N hydrochloric acid was heated under reflux for 19 hours. The mixture was concentrated in vacuo to give 6-chloro-2,3,4,5-letrahydro-1H-3-benzazepine as its hydrochloride salt, m.p. 214-215 ° C. The salt is treated with dilute sodium hydroxide solution to give 6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine base.

Example 3

A mixture of 0.52 g of 6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine, 0.34 g of allyl bromide, 0.6 g of potassium carbonate and 20 ml of 90% ethanol was added at room temperature. stir for an hour. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was extracted with ether (35 mL) and the ether extract was treated with isopropanolic hydrogen chloride solution to precipitate 3-allyl-6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. After recrystallization of the salt from anhydrous ethanol, the resulting 3-allyl-6-chloro-2,3,4,5-letrahydro-1H-benzazepine hydrochloride m.p. 248-249 ° C.

Example 4

The sides of 1.5 g of 6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine, 2.0 g of acetic anhydride and 20 ml of pyridine were stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue was washed with 3N hydrochloric acid and water, yielding 3-acetyl-6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 64-66 ° C. . The above amide was reduced with 50% excess lithium aluminum hydride in ether, refluxed for 6 hours. After decomposition of the excess reducing agent, the reaction mixture is filtered and the ethereal filtrate is dried over magnesium sulfate. The filtrate was treated with ethereal hydrogen chloride. The precipitated 6-chloro-3-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 274-275 DEG C. after crystallization from anhydrous ethanol.

Example 5

As described in Example 1, 2- {[2- (2-chlorophenyl) ethyl] methylamine] ethanol is 2 - {[2- (2-chlorophenyl) ethyl] ethylamino}. 6-chloro-3-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine substituted with -elanol or 2- (2- (2-chlorophenyl) ethyl 1-aHylamino 1-ethanol and 6-chloro-3-allyl-2,3,4,5-telrahydro-1H-3-berizazepine is obtained.

Example 6

Ingredients Quantity

6-chloro-2,3,4,5-telrahydro ro- 3-methyl-lH-3-benzazepine hydrochloride benzalkonium chloride twice with sodium hydrogen sulfides sterile sodium chloride solution (0.9%) U.S.P. 2.5g 0.02g 0.10 yrs To 100.00 ml The ingredients are dissolved in the sodium chloride solution. The solution is sterile filtered and packaged sterile. Two drops of the solution were applied to the eye three times a day. Example 7 Ingredients Quantity 6-Chloro-2,3,4,5-telrahydro-3-methyl-1H-3-benzazepine Purified White Vaseline, U.S.P. 1.0g 100.0 g Under sterile conditions, benzazepine is thoroughly processed with petroleum jelly and packaged. The balm is applied topically to the eyes four times a day. Example 8 Ingredients Quantity 6-chloro-2,3,4,5-tetrahydro- 3-methyl-lH-3-benza2epin- hydrochloride lactose 150 mg 350 mg The ingredients are thoroughly mixed and filled into a hard gelatin capsule. 1 capsule is administered four times daily. Example 9 Ingredients Quantity

6-Chloro-2,3,4,5-tetrahydro-3-methyl-1H-benzazepine hydrochloride 200 mg

-715 ingredients Quantity

calcium sulfate water (1/2) 150 mg saccharose 25 mg starch 15 mg talc 5 mg stearic 3 mg

The calcium sulfate water, sucrose and benzazepine are thoroughly mixed and granulated with 10% gelatin solution. The wet granulate is sieved, dried and then mixed with starch, talc and stearic acid, and sifted into a milled tablet.

Take 1 tablet three times a day.

Claims (3)

Claims A process for the preparation of a new benzazepine derivative of formula (I): wherein: R is allyl and X is halogen and pharmaceutically acceptable acid addition salts thereof (a) a compound of formula (II): wherein R and X are as defined herein; and Z represents a chlorine or bromine atom - cyclizing, or b) a compound of formula (III) wherein X is an alkylating agent of formula RY wherein R is as defined above and Y is a reactive halogen, and optionally converting the benzazepine-desalinazole of formula (I) obtained by process (a) or (b) into a pharmaceutically acceptable acid addition salt thereof. (Priority: 11/26/1982) 2. The process of claim 1, wherein the cyclization is carried out in a melt of aluminum chloride and ammonium chloride at high temperature. (Priority: November 26, 1982) 3. A process for the preparation of a pharmaceutical composition having α-antagonistic activity, which process comprises the preparation of a compound of formula (I) according to claim 1, wherein the substituents are as defined in claim 1 or a pharmaceutically acceptable acid thereof. the acid addition salt thereof is admixed with a carrier and / or excipient commonly used in the preparation of a pharmaceutical composition to form a pharmaceutical composition. (Priority: November 26, 1982) 4. A process for the preparation of a pharmaceutical composition having an? 2 antagonist activity comprising the steps of: R is C 1 -C 3 alkyl and X is halogen, or an acid addition salt thereof with a pharmaceutically acceptable acid - which is prepared by a) a compound of formula II 25 - wherein R and X are as defined in the scope and Z represents a chlorine or bromine atom - cyclizing, or b) a compound of formula III - wherein X is as defined in the scope (1) with an alkylating agent of the formula RY R is as defined and Y is reactive halogen - or (2) with an acylating agent of formula RCOY - in the formula R is methyl, ethyl, vinyl or methoxy; Y is as defined above, and the acylated product is reduced to a pharmaceutical composition in admixture with carriers and / or excipients conventionally used in the preparation of pharmaceuticals.